DESCRIPTION (adapted from the application) Hypertension is one of the most common diseases in America--being present in a 20% of the population. It is also one of the leading causes of morbidity and mortality in the United States, via its effects on heart, cerebrovascular and renal disease. Despite its prevalence, the underlying cause(s) of hypertension remain poorly understood. It is clear that there are environmental and hereditary genetic factors that predispose to the development of hypertension; identification of the genetic factors is made difficult, however, by the small effects of many genes coupled with overlying environmental factors. One approach to this problem has been to study single gene disorders that primarily affect blood pressure. The determinants of the molecular bases of glucocorticoid-remediable aldosteronism, Liddle's syndrome, Bartter's syndrome, Gitelman's syndrome and others has done to [sic] much to increase our understanding of renal physiology and the kidneys role in blood pressure regulation. In this project, we describe the discovery of a new form of mendelian hypertension caused by activating mutation in the mineralocorticoid receptor, the effector molecule for aldosterone in the distal nephron. Through characterization of the affected kindred and in vitro analysis of the mutant receptor, we will discern the mechanism by which the mutation activates mineralocorticoid receptor function. It is anticipated that this information will yield insight into normal receptor function, which may prove useful in drug design. By creating a mouse model of the disease, we hope to generate a mechanism to study the effects of a wide variety of steroid agonists and antagonists in vivo, and also to gain insight into the effects of the activated mineralocorticoid receptor in tissues other than the kidney. This project is designed to provide training in molecular and human genetics for the Principal Investigator and to enable him to develop a career in academic Nephrology with a focus on the molecular genetics of hypertension and renal disease.